Chronic pain is a devastating consequence of cancer affecting the majority of patients during the course of the disease. Conventional treatments use a variety of opioid regimens. However, in a significant number of patients these approaches fail due to the adverse effects of the medication. Therefore, the development of cancer pain treatments that do not cause the common side effects of systemic opioids remains an important goal. One known strategy to achieve this is the selective delivery of agents with opioid activity to the spinal cord. Recent advances in gene transfer technology, in particular Adeno-Associated Virus (AAV), suggest that gene therapy will be available in the near future for safe application in humans. The candidate has developed an artificial therapeutic gene, pre-pro-beta-endorphin (pp-beta-EP) for the treatment of pain by intrathecal gene delivery, has characterized its properties in vitro, and has demonstrated its short-term antinociceptive activity in a rat model of acute pain. The research plan proposes a strategy to achieve a long-term antinociceptive effect applicable to chronic cancer pain. Aim 1 is to test the hypothesis that intrathecally-injected rAAV will establish long-term transgene expression in the cells of the spinal cord and/or meningeal linings and that the serotypes 1, 2 and 5 will differ in the overall expression level and/or the range of cells transduced. The optimal vector characteristics defined by these experiments will be applied in Aim 2 to test the hypotheses that intrathecal pp-beta-EP provides 1) analgesic synergy with systemic morphine in a model of acute inflammatory pain and 2) a durable benefit in a model of chronic cancer pain. Aim 3 is to evaluate the immune response and other toxicity that may be elicited by intrathecal rAAV and the expression of pp-beta-EP. The candidate has a research background in neuroscience that he acquired prior to his recent clinical specialty training in internal medicine and subspecialty training in oncology. The proposed research will serve as a paradigm to train the candidate in the responsible conduct of research for a career as an investigator in the areas of gene therapeutics and drug development for chronic cancer pain targeting opioid- and non-opioid mediated mechanisms.